Objectives

EURIPIDES aims to develop in-vivo imaging biomarker of multidrug transporter function as a generic tool for the prediction, diagnosis, monitoring and prognosis of major CNS diseases, as well as to provide support and guidance for therapeutic interventions.

Resistance to drug treatment is an important hurdle in the therapy of many diseases of the central nervous system (CNS). Consequently, there is a pressing need to develop new and more effective treatment strategies. Whilst drug resistance in CNS diseases is multifactorial, there are two broad likely mechanisms:

1. target hypothesis: resistance to the desired pharmacological effects of CNS drugs occurs from alteration in the postulated target(s);
2. transporter hypothesis: inadequate access of CNS drugs to their targets across the blood-brain barrier (BBB) due to the overexpression or overactivity of multdrug transporters.

These multidrug transporters, of which P-glycoprotein (P-gp) is the most-widely studied, are found in and contributes to the normal BBB, and as efflux transporters, actively transport substrates (including multiple CNS drugs) against concentration gradients from the brain to blood and cerebrospinal fluid. This hampers the build up of adequate tissue levels of these drugs in the brain, greatly limiting their therapeutic efficacy. As such, the "transporter hypothesis" of drug resistance is applicable to a broad range of CNS drugs and patients with a variety of CNS diseases who critically depend on these drugs.
Efflux transporters may also influence brain elimination of Aß, the hallmark of Alzheimer’s disease (AD). Impaired multidrug transporter function with reduced clearance of Aß could lead to accumulation within the extracellular space, contributing to the pathogenesis of AD. We will determine the contribution of multidrug transporters to impaired brain uptake of drugs for the prediction of therapeutic responses, or the contribution of impaired transporter function to reduced clearance of toxic substances for the early in-vivo diagnosis of AD. Circumvention of pharmacoresistance, or increasing clearance, may involve inhibitors of multidrug transporters or sophisticated alternative therapies, but demonstration of overexpression or underactivity of transporter function is an essential and necessary first step. An in-vivo imaging biomarker of multidrug transporter function is essential for identifying altered transporter activity in individual patients.
Circumvention of pharmacoresistance, or increasing clearance, may involve inhibitors of P-gp transporters or sophisticated alternative therapies, but demonstration of overexpression or underactivity of transporter function is an essential and necessary first step. An in-vivo imaging biomarker of P-gp function is essential for identifying altered transporter activity in individual patients. If a relation between overexpression and therapy resistance, or underactivity and AD, can be demonstrated, such a biomarker will provide the means for predicting treatment response, or early diagnosis, in individual patients.